Halomethyl pregnenes



Patented Jan. 24, 1967 ice United States Patent Ofi 3,300,517 HALOMETHYL PREGNENES Riccardo Villotti and Albert Bowers, both of Mexico City, Mexico, assignors to Syntex Corporation, a corporation of Panama No Drawing. Filed Apr. 13, 1962, Ser. No. 187,224 12 Claims. (Cl. 260-3973) In the above formulas, R re-presnts hydrogen, hydroxy or an acyloxy group of less than 12 carbon atoms; X represents chlorine, bromine or iodine and Y represents fluorine, chlorine or bromine.

The acyl groups above referred to are derived from hydrocarbon carboxylic acids of less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, and pchloropropionate.

The compounds object of the present invention are progestational agents having anti-estrogenic, anti-androgenic, and anti-ovulatory activities. They are also hypnotic agents, useful in the treatment of premenstrual tension and possess anti-fungal and anti-bacterial properties.

The novel 16a-halornethyl-progesterone derivatives as wellas the 16a-halome thyl-3,B-chlro, fluoro and bromo A -pregnene compounds and l6a-halomethyl-A pregnadienederivatives unsubstituted at C-17a, are obtained by ii ill the method illustrated by the following sequence of re actions:

oorn i CH: i CH3 7 (i=0 e=o ja -on, p fi 0H, i i Q VI l c5; d:

In the above formulas, X has the same meaning as heretofore set forth and Y represents chlorine or bromine.

In practicing the process set forth above, l6a,l7u-cyclomethylene-A -pregnen-3fi-ol-20-one (I), obtained from I6a,l7e(4-3c-pyrazolo)-A -pregnen-3fi-ol-20-one acetate In accordance with the method of G. Nomin et al. in Bull. Soc. Chim., France, p. 550 (1960), followed by :onventional saponification of the acetoxy group at C3, ls oxidized with an 8 N chromic acid solution in acetone. The resulting crude 3-keto compound (II) dissolved in an inert organic solvent, preferably tetrahydrofuran, is ,reated at low temperature between and C. with a mixture of boron-trifiuoride etherate and concentrated hydrochloric acid. The resulting mixture is kept at 'oom temperature for a prolonged period of time in the order of 2 to 5 days to produce l6a-chloromethylarogesterone (III; X=Cl); under the conditions employed n the reaction, the A -double bond is shifted to give the A -3-keto compound. 7

When aqueous solutions of hydrogen bromide and iydrogen iodide are used instead of concentrated hydro- :hloric acid, there are produced 16u-bromomethyl and l6a-iodomethyl-progesterone (III; X=Br, I).

Upon treatment of 16a,l7a-cyclomethylene-A -pregnen- 3/3-ol-20-one (I) with phosphorous pentachloride or phosphorous pentabromide in an inert organic solvent, prefertbly in benzene solution, there is substituted for the 3- Iydroxy group, a bromine or chlorine atom (IV). The 'eaction of these intermediates with hydrochloric, hydro- Jromic or hydroiodic acid in the presence of boron triluoride and using tetrahydrofuran as solvent, affords the l6a-halomethyl-3B-chloro and 3fl-bromo-A -pregnene :ompounds (V). Thus for example, treatment of 160:, l7a-cyclomethylene-M-pregnen-3fl-ol-20-one with phosnhorous pentachloride in benzene solution gives --160c,l7ot :yclomethylene-3,8-chloro-A -pregnen-20-one, which upon teaction with hydrochloric acid in the presence of boron rifluoride produces 3;?chloro-16oc-chloromethyl-A preg- 1en-20-one.

The l6a-halornethyl-3fi-fluoro-A -pregnenes (X) are nbtained by converting the cyclomethylene compound (I) into its 3-tosylate by conventional esterification with tosyl chloride in pyridine solution; treatment of this :osylate with potassium acetate in methanol solution gives l6a,17a cyclomethylene 3,5 cyclo-6B methoxypregnan-ZO-one (VIII) which upon reaction with aqueous nydrofluoric acid in benzene solution at room temperature )r with anhydrous hydrogen fluoride in methylene chlo- :ide-tetrahydrofuran at low temperature, preferably bevween 0 and 80 C., for a period of time in the order )f 18 to hours, produces the 3,6-fiuoro-l6u,17a- :yclomethylene-A -pregnene (IX). By reaction of the atter compound with hydrochloric, hydrobromic or hylroiodic acid in mixture with boron trifiuoride, as de- ICl'lbGd previously, there are produced the correspondng 16e-halomethyl-Bfl-fluoro-pregnenes, i.e., 3 8-fluoro- [6a chloromethyl A pregnen-ZO-one, 3fi-flUOIO-l6oc- )romomethyl-A -pregnen-2O-one and 3,8-fiuoro-l6a-iodonethyl-A -pregnen-2O-one (X).

Treatment of the 3-tosylate of I with lithium chloride ii an aliphatic amide, preferably using dimethylacetamide 1S solvent, at reflux temperature for several hours, preferrbly during 5 hours, produces l6ot,l7u-cyclomethylenel -pregnadiene-20-one (VI). Upon reaction of this :ompound withhydrochloric, hydrobromic or hydroiodic lCld in mixture with boron triufluoride, under the same :onditions previously described, there are produced 16arhloromethyl-A -pregnadien-20-one, 16oc-brornomethyl- I -pregnadien-2O-one and 16tx-iodornethyl-A -pregna- :lien-20-one respectively (VII).

It is obvious that our method can be modified Within vide limits. Thus for example the l6ot-halomethyl group :an be introduced prior to the substitution of the 3-hylroxy for a halogen atom or the oxidation of the 3-hy- Iroxy-A -compound to the A -3-keto derivatives, and this )xidation may also be effected under ditIerent conditions.

The l6e-halomethyl-l7a-hydroxy (acyloxy) compounds of the present invention are obtained by the methods illustrated by the following series of reactions:

C Ila XIV XII (lam CH3 c=0 =0 IW OI'IgX T'CIMX Y- IIO- XV i XIII out om O=0 =0 IW tm Toni Toni);

TsO- I XVII XVI OCl'Ia CH3 CH3 i=0 i=0 I l....

I-CHZX 1cm): F

XVIII XIX In the above formulas, X and Y have the same meaning as heretofore set forth and R represents hydrogen or an acyl group of less than 12 carbon atoms.

In practicing the process set forth above, 16ot,170ccyclomethylene-A -pregnen-3fi-ol-20-one is treated with hydrochloric, hydrobromic or hydriodic acid in mixture with boron trifiuoride in an inert organic solvent, preferably using tetrahydrofuran, to give the corresponding 160thalomethyl derivatives (XI). By reaction of these compounds with acetic anhydride in the presence of p-toluenesulfonic acid, there are produced the l6a-halomethyl derivatives of A -pregnadiene-3[3,2O-diol diacetate which upon treatment with an organic peracid, preferably perbenzoic acid, there are produced the 5a,6 x;17 x,20a-bisoxido compounds (XII).

By reaction of the bis-oxido-l6ot-halomethyl compounds with dilute base, preferably using 2% methanolic potassium hydroxide solution at room temperature, the 17,20- epoxide ring is opened with simultaneous saponification at C-3. The 5a,60t-OXldO is then eliminated under Cornforth conditions, that is, by treatment with sodium iodide, sodium acetate and zinc dust .in acetic acid, thus producing the l6oc-ChlOIO-, bromo, and iodomethyl derivatives of A -pregnene-3fi,17a-diol-20-one (XIII).

Oxidation of these compounds with chromic acid in acetone solution followed by treatment with acid produces the A -3-keto grouping, thus giving rise to the 16a-h2tl0- methyl derivatives of l7a-hydroxy-progesterone (XIV; R =H). Upon .esterification of these compounds with acid anhydrides of less than 12 carbon atoms in benzene solution and in the presence of p-toluenesulfonic acid, there are produced the corresponding 17ot-acyloxy compounds (XIV; R =acyl).

Thus for example, when the above process is applied to 16a chloromethyl-A -pregnen-3;8 ol-20-one, there are produced successively 16a-chloromethyl-A -pregnadiene-3B-20-diol diacetate, 16a-chloromethyl-A pregnadiene-3/3,20-diol diacetate, 16a-chloromethyl-5a, 6a;17u,20ot-bisoxido-pregnane-36,20-dio1-diacetate, 16achloromethyl-5a,6a-oxido pregnane-3B,l7a-diol-20-one, 16:x-chloromethyl-A -pregnene-3B,17ot-diol-20-one, 16achloromethyl-17a-hydroxy-progesterone and l7ot-acyloxyprogesterone.

When 16a-chloromethyl, 16a-bromomethyl and 16cciodomethyl-A -pregnene-35,l7a-diol-20-one (XIII) are refluxed with phosphorous pentachloride or phosphorous pentabromide in benzene solution, there are produced the BB-chloroand 3p-bromo compounds (XV; R =H), which may be further esterified by the method previously described, thus affording the l7-acyloxy derivatives thereof (XV; R =acyl).

The 3fl-fluoro-17ot-hydroxy compounds are obtained from the 3-tosylates of 16a-halomethyl-A -pregnene-3l3, l7oc-di0l20-Ons (XVI) which are converted into the 3,5-cyclo-6fi-methoxy derivatives (XVII) by reaction with sodium acetate in methanol. U on treatment with hydrofluoric acid, using the methods hereinbefore described for the compounds lacking the l7tx-hydroxy group, there are produced 3fi-fluoro-16wchloromethyl-M-pregnen-17aol-20-one, 3,8-fluoro-l6a-bromom-ethyl-A -pregnen-17u-ol- 20-one and Zip-fluoro-16ot-iodomethyl-M-pregnen-l7a-ol- 20one (XVIII; R =H). By reaction of these compounds with acid anhydrides in benzene solution and in the presence of p-toluenesulfonic acid, there are produced the corresponding 17a-acyloxy compounds (XVIII; R =acyl).

By reaction of the tosylates (XVI) with lithium chloride in dimethylacetamide, using the method previously described for the Hot-unsubstituted compounds, there are produced the 16ot-halomethyl-A -pregnadien-17a-ol-20- one compounds (XIX; R =H) which are converted into the respective esters by the esterification method hereinbefore described.

The following examples serve to illustrate but are not intended to limit the scope of the present invention:

PREPARATION I To a stirred suspension of 30.5 g. of 16tx,17a-(4-3cpyrazolo)-A -pregnen-3fi-ol-20-one acetate in 160 cc. of anhydrous acetone there was added dropwise over a minutes period 15 cc. of freshly distilled boron trifluoride etherate. All the precipitate went to solution and evolu- A solution of 1 g., of l6a,l7ot-cyclomethylene-A pregnen-3fl-ol-20-one in cc. of tetrahydrofuran was treated at 0-5 C. with 2 cc. of freshly distilled borontrifluoride ether complex and 5 cc. of concentrated hydrochloric acid. The mixture was stirred for 10 minutes at said temperature and then kept at room temperature, ir the dark, for 4 days. The solution was then poured intc ice water and the product extracted with ethyl acetate the extract was washed with water, 5% sodium bicarbonate solution and water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. The resulting yellow oil was dissolved in benzene and filterec' through 10 g. of neutral alumina. The first cc. oi elution gave the pure 16a chloromethyl A pregnen- 3B-ol-20-one (recrystallized from acetone-hexane), whicl shows: M.P. 186-188 C. [OL]D+22 (CHCl Example II 2 cc. of freshly distilled boron trifluoride etherate was added to a solution of 16a,17a-cyc1omethylene-A pregnen-3,6-ol-20-one previously cooled to 0 C. While stirring the mixture was treated dropwise, over a 15 minutes period with 15 cc. of 47% hydriodic acid. The solution which developed an intense red color, was kept at room temperature for 36 hours in the dark. It was then poured into water and extracted with ethyl acetate. The organic extract was washed with water, 5% sodium bicarbonate solution, sodium thiosulfate solution and water, dried over anhydrous sodium sulfate and evaporated tc dryness.

The residue was chromatographed over fiuorisil. The fractions eluted with benzene gave 530 mg. of 16a-iodomethyl A pregnen 3,6 ol-20-one; M.P. 148-150 C.: [eth l-17 (CI-ICl Example III In the method of the preceding example there was met an aqueous saturated solution of hydrobromic acid instead of hydriodic acid. There was thus obtained 16abromomethyl-A -pregnen-3B-ol-20-one.

Example IV Toa solution of 5 g. of 16a,17a-cyclomethylene-A pregnen-3B-ol-20-one in 100 cc. of anhydrous benzene were added 5 g. of phosphorus pentachloride and the resulting mixture was refluxed for 1 hour in the absence of moisture. It was then cooled, poured into water; the benzene layer was washed with water several times, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from acetone gave 35 chloro l6oc,l7oc cyclomethylene-A -pregnen-20-one. M.P. 195-196 C. [d] +56 (CHCl Upon treatment of the above compound with boron trifluoride and hydrochloric acid in tetrahydrofuran solution, in accordance with the method of Example I, there was produced 3,8-chloro-l6a-chloromethyLM-pregnen-ZO- one, M.P. -1l2 C. [u] +l8 (CHCl Example V The preceding example was repeated but using phos phorus pentabro-rnide instead of phosphorus pentachloride in the first step, thus obtaining 3p-bromo-l6a,l7ot-cyclonethylene-A -pregncn-20-one and 3fi-bromo-16u-chloronethyl-A -pregnen-20-one.

Example VI A solution of 1.7 g. of 16u,17u cyclomethylene- A Jregnen-3B-ol-20-one, in 100 cc. of acetone was cooled to C. and treated under an atmosphere of nitrogen and vith stirring, with a solution of 8 N chromic acid (pre- Jared by mixing 26 g. of chromium trioxide with 23 cc. )f concentrated sulfuric acid and diluting with water to cc.), until the color of the reagent persisted in the nixture. It was stirred for minutes further at 05 C. 1nd diluted with water. The precipitate was collected, Mashed with water and dried under vacuum, thus affordng a crude product which was used for the next step without further purification.

The above crude compound was then treated with boron :rifluoride and hydrochloric acid in tetrahydrofuran by ollowing the method of Example I. The resulting oil vas chromatographed on neutral alumina. The fractions :luted With hexane-benzene (6:4) gave the pure 16a- :hloromethyl-A -pregnen-3,20-dione, M.P. l28131 C.; ja] +177 (CHCl In a similar manner but using 47% hydriodic acid and 1 saturated aqueous solution of hydrogen bromide instead )f hydrochloric acid, in accordance with the methods of Examples II and III, there were produced respectively 160:- odomethyl-progesterone and 16a bromomethyl progeserone.

Example VII A solution of 5 g. of 16a,17a-cyclomethylene-A -preg- 1en-35-ol-20-one in 40 cc. of pyridine was treated with 5 g. of tosyl chloride and the mixture kept at 0 C. overiight. It was then poured into water and the formed recipitate collected by filtration. Crystallization from tcetone-hexane gave the pure 16a,17a-cyc1omethylene- S pregnen 3B ol ZO-one tosylate, 'M.P. 158-160 C. jab-P23 (CI-ICl )t 224, 259, 273 m log 6 4.06, 1.70, 2.58.

A mixture of 4 g. of the above tosylate, 6 g. of potasium acetate, and 200 cc. of anhydrous methanol was reluxed for 6 hours. Then it was diluted with water and :xtracted with ethyl acetate. The organic extract was vashed with water, dried over anhydrous sodium sulfate md evaporated to dryness. The residue was dissolved n hexane, the insoluble material was filtered off and the l6X21I16 solution filtered through a column of 100 g. of leutral alumina, thus giving the .pure 16a,17a-cyclonethylene 3,5 cyclo-6fl-methoxy-pregnan-ZO-one, M.P. 8-91 C. [0L]D+125 (CHCl A solution of 2 g. of the latter compound in 100 cc. )f thiophene free benzene was treated at 0 C. with 40 cc. )f 40% aqueous hydrofluoric acid. The reaction mixture vas kept for 20 hours at room temperature and then :arefully poured into saturated sodium carbonate soluion. The benzene layer was separated and the aqueous ayer extracted several times with benzene The com- )ined benzene extract was washed to neutral, dried over tnhydrous sodium sulfate and evaporated to dryness. Fhe residue was chromatographed on 80 g. ofneutral tlumina. The fractions eluted with hexane-benzene 7:3 ttforded 1 g. of 16a,l7a-cyclomethylene-3fl-fluoro-A -preg- 1en-20-one, M.P. 160162 C. [Ot] +39 (CHCl Treatment of the foregoing compound with boron triluoride-hydrochloric acid in tetrahydrofuran in accordmce with the method of Example I, afforded 3/3-fiuoro- .6a-chloromethyl-A -pregnen 20 one, M.P. 99101 C. jtx] |-l1 (CHCl Example VIII To a solution of 1.5 g. of the tosylate of 160:,17oL-CYC10- nethylene-M-pregnen-3;3-ol20-one in 25 cc. of dimethyl tcetamide there was added 1.5 g. of lithium chloride and .he mixture refluxed for 5 hours under anhydrous condiions. It was then concentrated to a small volume under vacuum, sodium chloride solution Was added and the product extracted with ethyl acetate; the organic extract was washed to neutral, dried and evaporated. Chromatography of the residue on neutral alumina gave 16oc,l7u, cyclomethylene-A -pregnadien-20-one in pure form; M.P. 9193 C.; [u] -72 (CHCl )t 228, 234, 243 my log. 6 4.27, 4.28, 4.10.

Hydrochloric acid and boron trifluoride treatment of the preceding diene, in accordance with the method of Example I gave 16a-chloro-methyl-A -pregnadien-20- one, M.P. 82 C.; [a] -31 (CI-ICl A 228, 235, 242 my log 5 4.24, 4.25, 4.09.

Example IX Examples II and III were repeated but using 3fi-fluorol6a,l7ot-cyclomethyleneA -pregnen 20 one as starting material. There were thus obtained 3fl-flUOlO-l6a-i0d0- methyl-A -pregnen-20-one and 3/i-fiuoro-16a-bromomethyl-A -pregnen-20-one.

Example X A mixture of 6.6 g. of 16a-chloromethyl-A -pregnen-3,8- ol-20-one, 2.7 g. of p-toluenesulfonic acid and 300 cc. of acetic anhydride was submitted to a slow distillation during 5 hours. The residue was cooled and poured into iced water. The product was then extracted with ether, the extract washed successively with an aqueous solution of sodium carbonate and water to neutral, dried and evaporated to dryness. The residue consisted of 16oc-Chl0f0- methyl-A -pregnadien-35,20-diol-diacetate which was utilized in the following step without purification.

The above crude compound was dissolved in cc. of benzene and treated with a solution of perbenzoic acid in benzene (2.1 molar equivalents), at 0 C., for 20 hours. Water was then added, the organic layer separated, washed with an aqueous solution of sodium bicarbonate,

then with water, dried with anhydrous sodium sulfate and evaporated to dryness. The residue consisted of the crude 16a chloromethyl 5x,6u;17u,20a bis oxido-pregnan- 35,20-diol-diacetate.

This crude oxido compound was treated with 500 cc. of a 2% methanolic solution of potassium hydroxide at room temperature for 1 hour, the mixture was neutralized by addition of acetic acid, concentrated to small volume under reduced pressure, the product was precipitated by addition of ice water, filtered off, washed with water, dried and evaporated to dryness. The oily residue was dissolved in 80cc. of glacial acetic acid, there was added a mixture of 6 g. of sodium iodide, 1.6 g. of sodium acetate, 320 mg. of zinc and 2 drops of water. While cooling in an ice bath and stirring, there were added to the resulting mixture, 800 mg. of zinc dust in small portions. The stirring was continued for 6 hours and the temperature allowed to attain 25- C. f

The reaction mixture was filtered and the filtrate diluted with ice water, alkalized with sodium bicarbonate and extracted with ethyl acetate. The extract was washed to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was then chromatographed on 250 g. of neutral alumina, to give the pure 16a-chloron1ethyl-A -pregnene-3B,l7a-diol-20-one.

Example XI A solution of 1 g. of 16a-chloromethyl-A -pregnene-3B, l7ix-diol-20-one in 10 cc. of acetone was cooled to 0 C. and treated under an atmosphere of nitrogen and with stirring, with a solution of 8 N chromic acid in accordance with the method of Example VI until the color of the reagent persisted in the mixture. It was stirred for 5 minutes futher at 05 C. and diluted with water. The product was extracted with methylene chloride and the organic extract washed with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in 20 cc. of methanol 0.5 cc. of concentrated hydrochloric acid was added andthe mixture kept at 10 overnight. Water was added and the formed precipitate collected by filtration, washed to neutral and dried. Recrystallization from acetone-hexane gave the pure 16a-chloromethyl-17a-hydroxy-progesterone.

Example XII By following the methods of Examples X and XI 1611- bromomethyl-A -pregnen-3B-ol-ZO-one was converted into 160: bromomethyl A pregnene 3fi,17a diol-20-one and 16a-bromomethyl-l7a-hydroxy-progesterone.

By following the esterification method of Example XIII, the following compounds were converted into their corresponding esters, in accordance with the anhydride used as reagent.

Starting Material Acylating Agent Final Compound lfia-Chl oromethyl-ZiB-fiuoro-M-pregnen 1741-ol-20-one Propionieanhydride Prolpignate oi 1Ga-chloronlethy1-3B-fiuoro-A -pregnend7w -2 one. Caproate of 16a-ch10r0methyl-A -pregnadien-17a-oL2O- residue from ether-hexane produced 16a-chloromethyl- 16a-chl0romethyl-A -pregnadien-lh-ol-ZO-one Gaprcicanhydride one. lfia-bromornethyl-l7a-hydroxy-progesterone Aceticanhydride Acetate of16a-bromomethyl-lh-hydroxy-progesterone. ltie-chioromethyl-3B-chloro-A -pregnendh-olQO-one Caproicanhydride Caproate 0i16wehloromethyl 3fi-chloro-A pregnen-lh- Example XIII 20 We claim: To a solution of 500 mg. of l6a-chloromethyl-17a-hy- A Compound of the following formula: droxy-progesterone in 10 cc. of anhydrous benzene there CH3 were added 0.1 g. of p-toluenesulfonic acid and 1 cc. of =0 acetic anhydride and the mixture was allowed to stand t;... for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to effect hydrolysis of the excess anhydride. The benzene layer was separated and washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the 17a-acetoxy-progesterone.

In a similar manner but using caproic, propionic and cyclopentylpropionic anhydrides as esterifying agents, there were produced the caproate, propionate and cyclopentylpropionate of 16a chloromethyl 17a hydroxyprogesterone.

Example XIV Example XV 2 g. of 16a chloromethyl-A -pregnene-33,17a-di0l-2O- one was submitted to the reactions described in Example VII to produce successively 16a-chloromethyl-A -pregnene-3B,17a-diol-20-one 3-monotosylate, 16a-chloromethyl-n -cycl'o 6 methoxy-pregnan-l7a-ol-20-one, and 3B- fluoro-16a-chloromethyl-A pregnen-17a-ol-20-one.

Example XVI 1 of 16a-chloromethyl-A -pregnene-3B-l7a-diol-20- one Il-monotosylate was treated with lithium chloride in dimethyl acetamide, by following the method of Example VIII, to produce 16a-chloromethyl-A -pregnadien- 17a-ol-20-one.

Example X VII 1 v of l6a-brornon1ethyl-A -pregnene-3 8,l7a-diol-20- one was converted into 3 fl-chloro-16a-bromomethyl-A pregnen-l7a-ol-20-one, by treatment with phosphorus pentachloride in benzene solution in accordance with the method of Example IV.

A mixture of 500 mg. of the latter compound, 500 mg. of p-toluenesulf-onic acid monohydrate, 20 cc. of acetic acid and 10 cc. of acetic anhydride was kept for 24 hours at room temperature. It was then poured into water and stirred until the excess of anhydride had hydrolyzed.

wherein X is selected from the group consisting of chlorine, bromine and iodine; Y is selected from the group consisting of fluorine, chlorine and bromine; and R is selected from the group consisting of hydrogen, hydroxy and an hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms.

2. 3,8-chloro-l6a-chloromethyl-A -pregnene-20-one.

3. 3fl-bromo-16a-chloromet-hyl-A -pre-gnene-20-one.

4. Zip-fluoro-16a-chloromethylA -pregnene-20-one.

5. 3B-ehloro-16a-chloromet hyl-A -pregnen 17a ol- 20-one.

6. 3;B-chloro-16a-bromomethyl-A -pregnen 17a ol- 20-one.

7. 3t3-fiuoro 16a chloromethyl-A -pregnen 17oz ol- 20-one.

8. The acetate of 3B-chloro-16a-chloron1et-hyl-A -pregnen-l7a-ol-20-one.

9. A compound of the following formula:

wherein X is selected from the group consisting of chlorine, bromine and iodine; and R is selected from the group consisting of hydrogen, hydroxy and an hydrocarbon carboxylic acyloxy group of less than-l2 carbon atoms.

10. 16a-chlolromethyl-A -pregnadien-20-one. 11. 16a-chloromethyl-A -pregnadien-l7a-ol-20-one. 12. The caproate of 16a-chloromethyl-A -pregnadienl7a-ol-20-one.

References Cited by the Examiner UNITED STATES PATENTS 3,232,961 2/1966 Kaspar et al. 260397.3

LEWIS GOTTS, Primary Examiner.

H. F. FRENCH, Assistant Examiner. 

1. A COMPOUND OF THE FOLLOWING FORMULA 